Sunlight, ultraviolet (UV), exposure to the skin triggers cutaneous and systemic lupus (SLE) through an unknown mechanism. MRL (1Faslpr mutation) mice share features with human discoid lupus (DLE) and SLE (most notably lupus nephritis), and thus are valuable for understanding the pathogenesis of DLE, and its relationship to kidney disease. Colony Stimulating Factor 1 (CSF-1), the major macrophage (MX) growth factor, is pivotal in lupus nephritis in MRL-Faslpr mice. Our data suggest that CSF-1 is central to DLE in MRL-Faslpr mice. Enhancing systemic CSF-1 using CSF-1 transgenic MRL-Faslpr mice elevates circulating "inflammatory", activated monocyte (Mo), leading to an increase in MX in the skin and hastening the onset of DLE. Moreover, increasing cutaneous CSF-1 via implanting CSF-1 producing cells in the skin or UVB-exposure, triggers MX and apoptotic cell rich DLE in lupus-susceptible, MRL(1Faslpr), but not lupus-resistant mice. Conversely, CSF-1 deficient MRL-Faslpr mice exposed to UVB are resistant to DLE. Probing further, UVB stimulates CSF-1 expression by keratinocytes leading to the recruitment and activation of MX that, in turn, release mediators, which induce apoptosis in keratinocytes. Moreover, human translational findings indicate that CSF-1 is elevated in the serum/urine of lupus patients with DLE compared to healthy individuals. We propose to test the hypothesis that UVB-incited CSF-1 expression in the skin initiates MX mediated DLE. And in such hosts, UVB-incited circulating CSF-1 leads to DLE along with SLE. To test this hypothesis, we constructed novel, mutant MRL-Faslpr mice expressing distinct levels of CSF-1 (high, intermediate, none), individual CSF-1 isoforms, and reporter genes for identifying cells expressing CSF-1 and CSF-1 receptors (R) in tissues. The Specific Aims are: 1) To test the hypothesis that blocking CSF-1 is a therapeutic, and CSF-1 in the skin and/or serum is required for UVB triggered DLE in MRL-Faslpr mice. We will determine whether blocking the CSF-1R suppresses UVB-incited DLE, and explore the role of CSF-1 in the circulation and skin in mediating photosensitive DLE. 2) To test the hypothesis that aberrant MX responsiveness to CSF-1, and MX interactions with other immune cells, are required for UVB-incited DLE in MRL(1Faslpr) mice. We will determine whether MX are required/sufficient for UVB incited CSF-1 dependent DLE using genetic strategies, and determine whether aberrant MX responsiveness to CSF-1, leads to an influx of immune cells central to UVB-incited DLE. 3) To test the hypothesis that UVB triggers CSF-1 dependent, MX mediated SLE in MRL-Faslpr mice. We will determine whether UVB-incited CSF-1 triggers lupus nephritis, and determine whether circulating CSF-1 is the conduit between UVB-exposed skin and lupus nephritis. 4) To test the hypothesis that CSF-1 and MX are increased within skin lesions in patients with DLE and that CSF-1 generated in skin augments systemic (serum/urine) CSF-1 in DLE and SLE. Thus, these studies will provide insights into identifying new therapeutic targets for DLE/SLE by uncovering an essential piece of the sunlight/lupus puzzle. PUBLIC HEALTH RELEVANCE: Sunlight triggered skin and systemic disease is common in lupus, but poorly understood. We propose to pinpoint the role of Colony Stimulating Factor 1 (CSF-1) and CSF-1 receptor bearing cells (macrophage) in photosensitive lupus. By identifying an essential piece of the sunlight/lupus puzzle, these studies will provide insight into predicting the progression of lupus and identifying therapeutic targets to combat skin and systemic lupus.